This K99/R00 proposal presents a comprehensive training and research plan that will facilitate the career development of the Candidate (Justin Gass, PhD). During the mentored K99 phase of the award, Dr. Gass will receive training in cutting-edge laboratory techniques in neurophysiology and cellular biology that will expand and augment his existing expertise in the behavioral analysis of alcohol addiction. The research plan proposed for the independent R00 phase is based upon the Candidate's recent studies into the influence of alcohol- associated cues in relapse, and the proposed research will utilize the training obtained under the mentored phase. The techniques to be learned under the direction of the Mentor (Dr. Judson Chandler) will allow Dr. Gass to expand his behavioral studies into an investigation of the circuitry and neuronal networks that underly these behaviors. Most neuroscientists now consider the phenomenon of extinction to be "new" and "active" learning, and no longer view it as the simple "forgetting" of previously learned associations. Recent advances in the field of addiction research allow for the detailed analysis of changes in neuronal plasticity that are associated with learning. Therefore, the neural mechanisms that underlie the extinction of drug-seeking behavior can be investigated at the cellular level. Preliminary evidence indicates that allosteric modulation of type 5 metabotropic glutamate receptors (mGluR5) can facilitate extinction of alcohol-seeking behavior. Thus, the overall hypothesis of the research under this proposal is that extinction of alcohol-seeking behavior can be enhanced through modulation of mGluR5 receptors, and that this enhancement is associated with changes in plasticity within specific brain regions that regulate extinction behavior. This study will test the hypotheses that: 1) The extinction of alcohol-seeking behavior can be facilitated through positive allosteric modulation of the mGluR5 receptor;2) The enhancement of extinction of alcohol-seeking is mediated through complex neuronal activity involving the infralimbic cortex (IL-PFC) to nucleus accumbens (NAc) shell pathway;3) The enhancement of extinction of alcohol-seeking behavior is associated with changes in the morphology of dendritic spines within the IL-PFC and NAc shell;and 4) The positive allosteric modulation of mGluR5 during extinction training will attenuate the magnitude of cue-induced alcohol-seeking behavior. Additionally, the results from these studies will aid in the establishment of Dr. Gass's independent research program that will investigate how the neural mechanisms involved in the extinction of alcohol-seeking behavior can be used to develop pharmacological interventions that promote abstinence and reduce alcohol relapse. PUBLIC HEALTH RELEVANCE: Alcoholism is a chronic relapsing disorder that is associated with compulsive alcohol-seeking behavior. One of the main causes of alcohol relapse is the craving caused by environmental cues that are associated with alcohol. These cues are formed by normal learning and memory principles and the understanding of the brain mechanisms that help form these associations can lead to the development of drugs and/or behavior therapies that reduce the impact that these cues have on alcoholics.